We have used AAV vectors to generate, in rodents, phenomena that are associated with AIzheimer's disease (AD), and to counteract aspects of AD pathology. Neurofibrillary tangles (NFT) develop within weeks of surgical injection of an AAV vector carrying a human mutation in the gene encoding the microtubule-associated protein tau. Memory deficits were found a year after injection of a vector carrying familial AD mutations in amyioid precursor protein. Basal forebrain choiinergic neurons that are critical for memory, and which die in AD, have been protected against age- and injury-related loss of function by AAV vectors transducing the expression of nerve growth factor. We now propose to use this gene transfer technology to test in Aim 1 whether inibition of protein phosphatase 2A will result in dysfunction and pathology of tau in vivo. The activity of this enzyme has been found to be reduced in AD. Aim 2 will test whether overexpression of neuronal thread protein, found to be selectively and substantially elevated in AD, will induce any AD-reiated anatomical, behavioral, or biochemical pathology. This protein can form intracellular aggregates like tau and Abeta and is localized with pathological tau in AD brains. In Aim 3 we will test whether the localized overexpression of the amyloid beta (Abeta) protease neprilysin will interfere with amyloid deposition in mice transgenic for 2 human AD gene mutations that result in progressive accumulation of structures analogous to AD senile plaques. In Aim 4 we wiii use vectors to selectively overexpress individual species of Abeta that may either facilitate or interfere with accumulation of insoluble Abeta. This may help reveal why Abeta deposits fail to develop in a number of models in which it was expected but not found, and why it occurs naturally to some humans more than others. These studies are intended to increase our understanding of what determines whether AD occurs, in the absence of gene mutations. They also contribute to the development of future therapeutics, including potential gene therapy.